Signal transduction processes are major targets of drug discovery with G protein-coupled receptors being a primary site of action of many current therapeutic agents. Recent work, however, has shown that signaling pathways are not just linear chains of information but are webs of interacting regulatory molecules in which protein scaffolding, intracellular proximity, and inhibitory control are major determinants of signaling efficacy and specificity. The twenty Regulator of G protein Signaling (RGS) protein family members which inhibit G protein signaling represent a novel site of pharmacologic intervention but: 1) their physiological functions remain incompletely understood and 2) there are no reported small molecule inhibitors of RGS function. The identification of selective RGS inhibitors would provide both: 1) tools for the study of RGS function in cells and in vivo and 2) a starting point for therapeutic drug development. We have recently developed a robust cell- based functional assay for assessing RGS4 activity. This will be utilized in high-throughput screening in the MLPCN to identify compounds that selectively inhibit the activity of RGS4. The ultimate aim of this project is the identification of selective small molecule modulators of RGS action. This will provide important chemical tools and accelerate the development of novel therapeutics. PUBLIC HEALTH RELEVANCE: Much of commercial drug development currently targets a small subset of the human genome which is considered "druggable". In the present project, we are identifying chemicals that act on a new family of genes that play a key role in controlling brain function - the regulators of G protein signaling. Recent work implicates these proteins in depression, schizophrenia, epilepsy, and other disorders. By inhibiting or enhancing the function of RGS proteins, our long term goal is to develop novel drugs that will improve therapy of these conditions.